ArticleInternational journal of obesity (2005)2024
The endoplasmic reticulum stress protein GRP94 modulates cathepsin L activity in M2 macrophages in conditions of obesity-associated inflammation and contributes to their pro-inflammatory profile.
Article in International journal of obesity (2005), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 8 citations in OpenAlex.
- Cathepsins as Core Players in Obesity Pathogenesis: Emerging Therapeutic Targets.Biomolecules · 2026Review
- Lipid metabolism in pancreatic cancer treatment.World journal of clinical oncology · 2026Review
- Heat shock protein Gp96 (Grp94) in malaria: functional insights at the host-parasite interface and therapeutic perspectives.Frontiers in cell and developmental biology · 2026Review
- ATM interaction with GRP94 modulates oncogenic receptor expression and signaling and microglial activation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Review
- Glucose-regulated protein 94 (Grp94/gp96) in viral pathogenesis: Insights into its role and therapeutic potentials.European journal of medicinal chemistry · 2025Review
- Inflammation Promotes Proteolytic Processing of the Prohormone Chromogranin A by Macrophages.Journal of the Endocrine Society · 2025Article
- Targeting lipid metabolism: novel insights and therapeutic advances in pancreatic cancer treatment.Lipids in health and disease · 2025Review
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND/
objectivesAdipose tissue macrophages (ATM) are key actors in the pathophysiology of obesity-related diseases. They have a unique intermediate M2-M1 phenotype which has been linked to endoplasmic reticulum (ER) stress. We previously reported that human M2 macrophages treated with the ER stress inducer thapsigargin switched to a pro-inflammatory phenotype that depended on the stress protein GRP94. In these conditions, GRP94 promoted cathepsin L secretion and was co-secreted with complement C3. As cathepsin L and complement C3 have been reported to play a role in the pathophysiology of obesity, in this work we studied the involvement of GRP94 in the pro-inflammatory phenotype of ATM.
methodsGRP94, cathepsin L and C3 expression were analyzed in CD206 + ATM from mice, WT or obesity-resistant transgenic fat-1, fed a high-fat diet (HFD) or a standard diet. GRP94 colocalization with cathepsin L and C3 and its effects were analyzed in human primary macrophages using thapsigargin as a control to induce ER stress and palmitic acid (PA) as a driver of metabolic activation.
resultsIn WT, but not in fat-1 mice, fed a HFD, we observed an increase in crown-like structures consisting of CD206 + pSTAT1+ macrophages showing high expression of GRP94 that colocalized with cathepsin L and C3. In vitro experiments showed that PA favored a M2-M1 switch depending on GRP94. This switch was prevented by omega-3 fatty acids. PA-induced GRP94-cathepsin L colocalization and a decrease in cathepsin L enzymatic activity within the cells (while the enzymatic activity in the extracellular medium was increased). These effects were prevented by the GRP94 inhibitor PU-WS13.
conclusionsGRP94 is overexpressed in macrophages both in in vivo and in vitro conditions of obesity-associated inflammation and is involved in changing their profile towards a more pro-inflammatory profile. It colocalizes with complement C3 and cathepsin L and modulates cathepsin L activity.
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